The absorption, distribution, metabolism, and excretion (ADME) pharmacokinetics studies form an efficacy benchmark for various drug compounds. The evaluation of these pharmacological properties is critical for the selection of a new drug candidate during drug discovery and development.
ADME assays are conducted to make a go-no-go decision regarding drug candidate selection and movement into late-stage preclinical and clinical programs. Regular improvements in the ADME properties are achieved during lead optimization while keeping the selectivity and potency of the chemical drug lead intact. It, however, is plausible to have chemically efficacious compounds with acceptable ADME properties but decreased in vivo potencies.
Absorption
Drugs administered orally are absorbed in the digestive tract and reach the site of action through the bloodstream. The extent of drug absorption and corresponding concentration at the site of action is affected by various aspects such as reduced gastric emptying time, compound solubility, chemical instability, intestinal transit time, etc.
Absorption quality of a drug compound in ADME studies is primarily assessed to analyze the bioavailability of the drug at the site of action. If an orally administered drug is poorly absorbed in the systemic circulation in the human body, discrete methods of administration are tested, such as inhalation or intravenous intake. Hence, the route of drug administration plays an essential role in the identification of drug efficacy.
Distribution
Once absorbed, the drug compound is required to reach the site of action. From the bloodstream, the most common distribution medium, the drug compound reaches various organs and muscles.
Metabolism
Most small molecules transform into metabolites through metabolic breakdown involving specific enzymatic systems. Some metabolites are inert and while others are active. Thus, metabolism deactivates parent drug’s administered dose leading to a reduced drug impact in case of inactive metabolites. However, it enhances the bioavailability of the drug compound at the site of action if the metabolite is active.
Excretion
The body excretes metabolites and remaining drugs through the kidneys and other organs. If excretion is incomplete, the accumulation of foreign substances in the body can adversely influence various metabolic processes.
Toxicity
The ADME studies often include toxicity study as the last phase. It calculates the extent to which the administration of a drug compound can harm the human body or organisms. Here, organisms may refer to animal or organism substructure such as cells.
Role of Plasma Protein Binding Assay in ADME Studies
The binding pattern of the drug compound to the plasma proteins are a major contributing factor to the distribution and overall efficacy of the drug. Generally, the drug concentration at the site of action is limited when the binding between plasma protein and drug compound is sturdy. Hence, the efficacy of the corresponding compound also reduces. Thus, understanding the impact of free drug in the plasma or plasma protein binding is necessary for drug discovery as assists in finding the associated in vivo efficacy of the drug product.
The degree of plasma protein binding of a drug compound can be determined using Rapid Equilibrium Dialysis (RED). Plasma spiked with the drug is placed in the central chamber of the RED device, and the isotonic sodium phosphate solution is placed in the peripheral chamber. The sample is incubated at 37 °C for 4 hours, and the free compound equilibrium is attained by diffusing unbound compound through the dialysis membrane of the RED device.
ADME Assay Development during Drug Discovery, Preclinical, and Clinical Phases
The in vitro and in vivo ADME studies offer a deep understanding of Pharmacokinetic (PK) properties of the selected drug candidates. Assessing the potential of the compound in the early drug development phases offer desirable efficacy and safety profile of the drug candidate.
The bioavailability of the drug compound is influenced by various factors such as permeability, solubility, metabolism, and protein binding. Different ADME assays are utilized to determine the bioavailability of the given test sample such as protein binding assays, aqueous solubility, etc.
Metabolism, on the other hand, proves the therapeutic index of the compound by use of ADME assays such as cytochrome P450 induction and inhibition assays, UGT phenotyping, etc.
The ADME assays used for in vitro and in vivo studies as under:
- Aqueous solubility
- Lipophilicity (Log D) and Log P
- CaCo-2 and MDCK permeability
- PAMPA
- Plasma and serum stability
- Liver microsomes stability
- CYP Time-dependent inhibition
- CYP450 inhibition
- CYP450 phenotyping
- Blood-plasma distribution
- Plasma protein binding
- Brain protein binding
Why choose NorthEast BioLab for Your ADME Studies?
The assessment of ADME pharmacokinetics is critical for various stages of drug development, such as discovery, preclinical, and clinical phases. ADME and toxicity studies offer a clear knowledge of the metabolism and safety profile of a feasible drug candidate, enabling proper execution of clinical trials. However, it is necessary to conduct these studies in a controlled environment, which is why our scientists rely on their industry knowledge and FDA approved standards for the in vivo and in vitro studies.
Owing to our in-depth understanding of the right drug development process, we even collaborate with your other vendors to ensure complete transparency. From the drug candidate selection based on various ADME pharmacokinetic factors to drug compound assessment in human volunteer or in vivo trials, our lab scientists and analysts closely monitor the therapeutic index of the drug compound. This objective lens helps ensure that the selected drug compound has the correct, safe concentration required for therapeutic effect at the site of action for an illness or disease.